Amide bonds are ubiquitous in nature and represent one of the most important chemical bonds that constitute biomolecules. Amides are present in the backbone of peptides and proteins, and are an important component of polynucleotides. Consequently, the development of synthetic methods for the formation of amide bonds has long preoccupied chemists.
Despite the favorable thermodynamic stability of the resulting amide bond, the dehydrative reaction between a free carboxylic acid and an amine is inhibited by a large activation energy. For instance, the initial formation of a stable ammonium carboxylate salt deters the dehydration step. The salt intermediate collapses to provide the amide product only at very high temperatures (typically over 160° C.) that are incompatible with many functionalized molecules. Consequently, this important reaction continues to challenge chemists. An alternative method for the direct synthesis of an amide bond from a free carboxylic acid and amine in a simple, green and economical fashion would be a very useful tool.
Most current amide bond-forming methods involve the use of large excesses of expensive and toxic reagents such as carbodiimides, carbonyldiimidazole, phosphonium salts, and others, to dehydrate or activate the carboxylic acid. These coupling agents and their associated co-reagents (bases, supernucleophiles, and other additives) generate large amounts of wasteful by-products that tend to complicate the isolation of the desired amide.
The direct formation of amide bonds has been known since 1858 (described in Benz, G. In Comprehensive Organic Synthesis, Vol 6; Trost B. M., Fleming I., Heathcock C. H. Pergamon press: New York, 1991, Chap. 2.3). Catalysts that have been used for amidation reactions between carboxylic acids and amines include: TiCl4 (Carlson et al. Acta Chem. Scand. Ser. B. 1988, 28); Ti(O-i-Pr)4, (Helquist et al. Tetrahedron Lett., 1988, 59, 3049); Ph3SbO/P4S10 (Matsuda et al. J. Org. Chem. 1991, 56, 4076); Sb(OEt)4 (Yamamoto et al. J. Am. Chem. Soc. 1996, 118, 1569); and ArB(OH)2 (Ishihara et al. J. Org. Chem. 1996, 61, 4196).
The ArB(OH)2 catalysts reported in Ishihara et al. (id) include those where Ar is 3,4,5-trifluorophenyl, 3-nitrophenyl, 3,5-di-(trifluoromethyl)phenyl, 4-trifluoromethylphenyl, phenyl, 2,4,6-tri-(trifluoromethyl)phenyl and 2,3,4,5-tetrafluorophenyl. The reactions were performed at temperatures of about 110° C. (refluxing toluene) with a catalyst loading of 5 mol % and with the removal of water using 4 Å molecular sieves in a Soxhlet thimble. A solid phase version of these catalysts was reported by Latta et al. (Synthesis. 2001, 11, 1611-1613), however the procedure of Latta et al. also requires very high temperatures.
A room temperature catalytic electrophilic activation of carboxylic acids was previously described using ortho-substituted phenyl boronic acids (Hall et al. PCT Patent Application Publication No. WO 2009/030022).
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